Prenatal SARS-CoV-2 infection is associated with higher rates of pregnancy and birth complications, despite that vertical transmission rates are thought to be low. Here, multi-omics analyses of human placental tissues, cord tissues/plasma, and amniotic fluid from 23 COVID-19 mother-infant pairs revealed robust inflammatory responses in both maternal and fetal compartments. Pronounced expression of complement proteins (C1q, C3, C3b, C4, C5) and inflammatory cytokines (TNF, IL-1α, and IL-17A/E) was detected in the fetal compartment of COVID-19-affected pregnancies. While ~26% of fetal tissues were positive for SARS-CoV-2 RNA, more than 60% of fetal tissues contained SARS-CoV-2 ORF8 proteins, suggesting transplacental transfer of this viral accessory protein. ORF8-positive fetal compartments exhibited increased inflammation and complement activation compared to ORF8-negative COVID-19 pregnancies. In human placental trophoblasts in vitro, exogenous ORF8 exposure resulted in complement activation and inflammatory responses. Co-immunoprecipitation analysis demonstrated that ORF8 binds to C1q specifically by interacting with a 15-peptide region on ORF8 (C37-A51) and the globular domain of C1q subunit A. In conclusion, an ORF8-C1q-dependent complement activation pathway was identified in COVID-19-affected pregnancies, likely contributing to fetal inflammation independently of fetal virus exposure.

中文翻译：

---

经胎盘 SARS-CoV-2 蛋白 ORF8 与补体 C1q 结合以触发胎儿炎症。


产前 SARS-CoV-2 感染与较高的妊娠和分娩并发症发生率有关，尽管垂直传播率被认为很低。在这里，对 23 对 COVID-19 母婴的人类胎盘组织、脐带组织/血浆和羊水的多组学分析揭示了母体和胎儿隔室中强烈的炎症反应。在受 COVID-19 影响的妊娠的胎儿隔室中检测到补体蛋白 （C1q、C3、C3b、C4、C5） 和炎性细胞因子 （TNF、IL-1α 和 IL-17A/E） 的显着表达。虽然 ~26% 的胎儿组织对 SARS-CoV-2 RNA 呈阳性，但超过 60% 的胎儿组织含有 SARS-CoV-2 ORF8 蛋白，表明这种病毒辅助蛋白经胎盘转移。与 ORF8 阴性 COVID-19 妊娠相比，ORF8 阳性胎儿隔室表现出炎症和补体激活增加。在体外人胎盘滋养层细胞中，外源性 ORF8 暴露导致补体激活和炎症反应。免疫共沉淀分析表明，ORF8 通过与 ORF8 上的 15 肽区 （C37-A51） 和 C1q 亚基 A 的球状结构域相互作用特异性结合 C1q。总之，在受 COVID-19 影响的妊娠中发现了 ORF8-C1q 依赖性补体激活通路，可能独立于胎儿病毒暴露导致胎儿炎症。